Exome sequencing and whole genome sequencing (ES/WGS) are rapidly emerging as important tools in human genetics research. Unlike conventional approaches, ES/WGS can putatively identify all functional variation in the entire coding sequence of a research participant. As a result, both the number and scope of findings with clinical utility are substantially greater than anticipated by existing guidelines and traditional approaches to return of results. Our objective is to investigate: (1) the best ways to communicate with research participants about what kinds of ES/WGS results could be returned to them; (2) the most effective way to return different kinds of ES/WGS results to participants across a range of study populations; and (3) the impact on study participants of receiving results from ES/WGS studies. We will take advantage of an existing collaboration between genome scientists and ethicists who together are using ES/WGS to discover variants/genes underlying Mendelian and complex diseases in both pediatric and adult populations. Together with experts in clinical genetics, genomics, genetic counseling, and biomedical informatics we will compare the use of traditional approaches for the return of results to the use of an innovative web-based tool that enables longitudinal personalized management of ES results and dynamic engagement of research participants. The proposal has four specific aims: (1) assess and describe participant preferences about return and management of ES results across a broad range of study populations; (2) assess annotated variants in ten candidate genes from participant ES data (annotated exome data are already available on all participants to be studied herein) to identify mutations of potential clinical utility and make recommendations about which results to offer for return; (3) compare the effectiveness of an innovative web-based tool for results management to return of results from a single face-to-face session with a genetic counselor; and (4) assess the psychological, social and health-related impact of the return of ES results using validated survey tools and interviews, and by a comparison of outcomes and satisfaction. We will use our results to develop a comprehensive framework and a set of guidelines and policies for return of results from ES/WGS studies.